Numerous medical applications of collagen have already been described, whether in the form of pastes, for example for filling purposes, fluid or solid formulations, such as films or compresses, or in the form of various implants. In fact, only animal collagen is generally used.
The preparation of human collagen, which would be preferable to animal collagen for the avoidance of immunological and inflammatory reactions, is possible from human skin tissue. However, it is made very difficult because the removal of human tissue from corpses poses considerable ethical problems and requires expensive tests in order to eliminate the risk of the transmission of infectious, viral or other diseases. The preparation of human collagen from placentas is expensive, complex and difficult to organize. The preparation of human collagen by modern methods of genetic recombination or of cell culture is also very expensive, which will certainly hamper the commercial development of this product.
Globin that is insoluble at physiological pH and not chemically modified has recently been described as an alternative to collagen in some medical applications: (patent FR 2854801). Globin is the protein which constitutes haemoglobin, which itself contains 4 peptide chains (2α chains and 2β chains) each associated with a haem. Haem is formed by a tetrapyrrole structure containing 1 positively charged iron atom. There are 4 haems per molecule and they are responsible for the red colour of haemoglobin.
Processes for the preparation of globin have been known for a very long time and were developed for the purpose of application in foodstuffs or for the preparation of injectable pharmaceutical solutions.
Unlike haemoglobin, which is completely soluble at physiological pH, globin is remarkably insoluble under the same conditions. The insoluble, or poorly soluble, character of globin under physiological conditions has hitherto hampered the development of its medical applications as plasma substitutes. This is why the majority of published tests have sought to prepare soluble derivatives of globin at physiological pH, especially by succinylation using succinic anhydride or by acetylation using acetic anhydride, or by hydrolysis of the amide groups at alkaline pH. All of those processes increase the negative charge of globin and reduce its isoelectric pH, rendering the globin soluble at neutral pH.
An injectable product combining a soluble preparation of acidic globin with insulin has been developed, patented and marketed: REINER (1939); REINER et al. (1939). After injection, the product permits gradual release of insulin from this complex: RABINOWITCH et al. (1947); BERG et al. (1953). The globin of which this preparation is composed is not chemically modified; it is insoluble at physiological pH, present at a low concentration, and it is neither the active element nor the main element of this product.
Recently, new materials and new medical applications based on globin that is insoluble at neutral pH under physiological conditions have been described and have been the subject of a family of patents arising from patent FR 2854801.
However, it seemed to us that it would be of value to be able to manufacture biomaterials that are soluble or insoluble as desired, at physiological pH, using one and the same starting material derived from globin.
The present invention proposes to provide new materials and preparations implantable in the organism which are prepared from globin that is chemically modified to be soluble at physiological pH. These implants do not have the disadvantages or limitations of the known materials and formulations, for example of collagen, sodium hyaluronate, or the like, in particular owing to the ability to prepare them from the blood of the patient to be treated or from one of his matches and owing to their natural and completely tolerated character.